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Peripheral tissues reprogram CD8+ T cells for pathogenicity during graft-versus-host disease
Pedro Santos e Sousa, … , Clare L. Bennett, Ronjon Chakraverty
Pedro Santos e Sousa, … , Clare L. Bennett, Ronjon Chakraverty
Published March 8, 2018
Citation Information: JCI Insight. 2018;3(5):e97011. https://doi.org/10.1172/jci.insight.97011.
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Research Article Immunology Transplantation

Peripheral tissues reprogram CD8+ T cells for pathogenicity during graft-versus-host disease

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Abstract

Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic stem cell transplantation induced by the influx of donor-derived effector T cells (TE) into peripheral tissues. Current treatment strategies rely on targeting systemic T cells; however, the precise location and nature of instructions that program TE to become pathogenic and trigger injury are unknown. We therefore used weighted gene coexpression network analysis to construct an unbiased spatial map of TE differentiation during the evolution of GVHD and identified wide variation in effector programs in mice and humans according to location. Idiosyncrasy of effector programming in affected organs did not result from variation in T cell receptor repertoire or the selection of optimally activated TE. Instead, TE were reprogrammed by tissue-autonomous mechanisms in target organs for site-specific proinflammatory functions that were highly divergent from those primed in lymph nodes. In the skin, we combined the correlation-based network with a module-based differential expression analysis and showed that Langerhans cells provided in situ instructions for a Notch-dependent T cell gene cluster critical for triggering local injury. Thus, the principal determinant of TE pathogenicity in GVHD is the final destination, highlighting the need for target organ–specific approaches to block immunopathology while avoiding global immune suppression.

Authors

Pedro Santos e Sousa, Séverine Ciré, Thomas Conlan, Laura Jardine, Claire Tkacz, Ivana R. Ferrer, Cara Lomas, Sophie Ward, Heather West, Simone Dertschnig, Sven Blobner, Terry K. Means, Stephen Henderson, Daniel H. Kaplan, Matthew Collin, Vincent Plagnol, Clare L. Bennett, Ronjon Chakraverty

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Figure 4

Blood- and skin-correlated T cell modules are also identifiable in human patients.

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Blood- and skin-correlated T cell modules are also identifiable in human...
(A) Bar graph showing the B6→129 and F→M WGCNA-defined modules ordered according to their correlation with the blood or the epidermis. Red line indicates P = 0.01. (B) Graph showing the FDR q value (bars) and NES (color code) calculated by GSEA, comparing the enrichment for the blood- and skin-correlated B6→129 and F→M WGCNA-defined modules in the blood (blue) and epidermis (red) samples of human patients at the onset of acute skin GVHD. FDR, false discovery rate; GSEA, gene set enrichment analysis; GVHD, graft-versus-host disease; NES, normalized enrichment score; SLO, secondary lymphoid organs; TO, target organs; WGCNA, weighted gene coexpression network analysis.

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